This application is a 371 of PCT/EP99/08999, filed Nov. 23, 1999 published as WO 00/32198, Jun. 8, 2000.
The present invention relates to the use of a specific class of compounds for the prevention of damages and mortality caused by global cerebral ischemia and ischemia-reperfusion and for the treatment of acute and chronic cerebrovascular diseases.
When cerebral blood flow is reduced to about 10-20% of the normal flow, neurons and astrocytes consume their cellular energy metabolites and lose their capacity of regulating transmembrane ionic gradients (Hansen A. J., Physiol. Rev. 1985; 65:101-148). As a consequence, ionic homeostasis results to be jeopardized and all types of cells degenerate, as a consequence of the ischemic infarction (Ginsberg M., The Neuroscientist, 1995; 1:95-103). It has been estimated in rodents that a cerebral ischemic injury reaches its peak 4-8 hours after the arterial occlusion, but it is possible to reduce the extent of the infarction without changing the duration or the intensity of the insult. As a matter of fact, the ischemic injury can be alleviated by the modulation of a wide range of parameters, such as: closing calcium channels associated to NMDA receptor (Siesjo B. et al., Ann. Thorac. Surg. 1995; 59:1316-1320); reducing intracellular free calcium (Tymianski M. et al., Neuron 1993; 11:221-235); reducing production of free radicals (Chan P., Brain Pathol. 1994; 59-65); lowering brain temperature (Dietrich W. et al., Cellular and molecular mechanism of ischemic brain damage. Siesjo B., Wieloch T., eds., 177-198. Philadelphia: Lippincott-Raven).
Adenosine, an endogenous nucleoside that binds to purinoceptors of P1 type, exerts a neuromodulating activity in several areas of the central nervous system of mammals. It is moreover involved in the regulation of cerebral blood flow (Rudolphi K. A. et al., Cerebrovascular brain metabolism reviews, 1992; 4:346-369; Rudolphi K. A. et al., Trends in Pharmacol. Sci. 1992; 13:439-445; Fredholm B. B., Neuroprotective agents and cerebral ischemia, Green A. R., Cross A. J. eds., pp. 259-280, Academic Press 1997, San Diego). Adenosine acts as a neuroprotective agent during the onset of cerebral ischemic damage. It uses several mechanisms such as, for instance: inhibition of the neuronal activity by the reduction of both the excitatory amino acid release and the calcium ion influx; stabilization of the membrane potential by hyperpolarization; inhibition of the free radicals production; increase in blood supply by vasodilatation; inhibition of platelet aggregation and adhesion of neutrophils to endothelial cells (Miller, L. P., Hsu C., J. of Neurotrauma, 1992; 9:S563-S577; Rudolphi K. A. et al., Trends in Pharmacol. Sci. 1992; 13:439-445).
Unlike the direct involvement of P1purinoceptors in the neuroprotective action played by adenosine, as at today little is known about a potential role of P2 purinoceptors (preferred for ATP; Burnstock G.; Neuropharmacology 1997; 36, 11427-1139) in the onset or protection from cerebral ischemic damage.
U.S. Pat. No. 5,733,916 describes a method for the treatment of the damages caused by ischemia-reperfusion in organs intended for transplant or surgery. This method concerns the administration of an antagonist of the A1 adenosine receptor and/or an antagonist of P2 purinoceptors. In particular, said antagonist for P2 receptors is PPADS, utilized in described cases of lung ischemia. U.S. Pat. No. 5,733,916 concerns ischemia-reperfusion and in particular lung ischemia, which affects an organ that requires a drastic reduction in the blood supply, when it is subjected to transplant or surgery. Such drastic reduction causes ischemic damages that may be localized and severe. According to what is reported in U.S. Pat. No. 7,733,916, such damages are advantageously treated by administering PPADS (15 mg/kg) 30 minutes before ischemia, and/or an antagonist of the A1 adenosine receptor. U.S. Pat. No. 5,733,916 describes intravenous administration of PPADS, which allows the compound to reach the lung wherein ischemia has taken place.
Object of this invention is to provide a class of compounds that allow to reduce the damages and the mortality caused by cerebral ischemic injury and reperfusion-induced ischemia, with the ensuing possibility of an effective treatment of acute and chronic cerebrovascular diseases.
Another object of this invention is to provide a class of compounds allowing to modulate several physiological functions, for instance energy metabolism, neuronal activity, cell survival.
Another object of the present invention is to provide a class of compounds allowing to prevent the mortality caused by ischemic stress either induced or suffered. Another object of the present invention is to provide a class of compounds allowing to reduce mortality caused by cerebral ischemic insult and such as to be easily administered and to pass the blood-brain barrier. Still another object of the present invention is to provide a class of compounds representing a valid pharmacological alternative to agents that are already used for the treatment of ischemic insult, reperfusion and acute and chronic cerebrovascular diseases, either induced or suffered.